Download Relapsing polychondritis

Relapsing polychondritis
Author: Professor Alexandros A. Drosos1
Creation Date: November 2001
Update: October 2004
Scientific Editor: Professor Haralampos M. Moutsopoulos
1
Department of Internal Medicine, Section of Rheumatology, Medical School, University of Ioannina, 451
10 Ioannina, GREECE. [email protected]
Abstract
Keywords
Disease name and synonyms
Diagnostic criteria / Definition
Differential diagnosis
Prevalence
Laboratory findings
Prognosis
Management
Etiology
Genetic findings
Diagnostic methods
Genetic counseling
Unresolved questions
References
Abstract
Relapsing polychondritis (RP) is a multisystem inflammatory disease of unknown etiology affecting the
cartilage. It is characterized by recurrent episodes of inflammation affecting the cartilaginous structures,
resulting in tissue damage and tissue destruction. All types of cartilage may be involved. Chondritis of
auricular, nasal, tracheal cartilage predominates in this disease, suggesting response to tissue-specific
antigens such as collagen II and cartilage matrix protein (matrillin-1). The patients present with a wide
spectrum of clinical symptoms and signs that often raise major diagnostic dilemmas. In about one third of
patients, RP is associated with vasculitis and autoimmune rheumatic diseases. The most commonly
reported types of vasculitis range from isolated cutaneous leucocytoclastic vasculitis to systemic
polyangiitis. Vessels of all sizes may be affected and large-vessel vasculitis is a well-recognized and
potentially fatal complication. The second most commonly associated disorder is autoimmune rheumatic
diseases mainly rheumatoid arthritis and systemic lupus erythematosus . Other disorders associated with
RP are hematological malignant diseases, gastrointestinal disorders, endocrine diseases and others.
Relapsing polychondritis is generally a progressive disease. The majority of the patients experience
intermittent or fluctuant inflammatory manifestations. In Rochester (Minnesota), the estimated annual
incidence rate was 3.5/million. The peak age for disease onset is the fifth decade, although cases have
been reported at both extremes of life. The treatment of choice is prednisone; however,
immunosuppressive drugs seem to have an additional value. Methotrexate was found to be an efficacious
and well-tolerated steroid sparing drug.
Keywords
Relapsing polychondritis; cartilage; chondritis; auricular; nasal; laryngotracheal; collagen type II; matrillin1; vasculitis; autoimmune diseases; malignant disorders.
Disease name and synonyms
Relapsing polychondritis;
auricular chondritis;
nasal chondritis;
polychondropathia.
Drosos, A.A. Relapsing polychondritis. Orphanet encyclopedia, October 2004.
http://www.orpha.net/data/patho/GB/uk-RP.pdf
1
Diagnostic criteria / Definition
Relapsing polychondritis (RP) was first described
in 1923 by Jaksch-Wartenhorst under the term of
“polychondropathia” and was considered as a
degenerative disease (1). It is an uncommon
multisystemic disorder of unknown etiology
affecting young adults. It is characterized by
recurrent episodes of inflammation affecting the
cartilaginous structures, resulting in tissue
damage and tissue destruction. All types of
cartilage may be involved such as: the elastic
cartilage of the ears and nose, the hyaline
cartilage of peripheral joints, the fibrocartilage of
the axial skeleton and the cartilage of the
tracheobronchial tree. RP can also affect other
proteoglycan-rich structures like the eye, heart,
blood vessels and inner ear. Thus, patients with
RP present with a wide spectrum of clinical
symptoms and signs that often raise major
diagnostic dilemmas (2-5).
In the majority of patients, RP has a fluctuating
but progressive course in which recurrent bouts
of inflammation lead to the permanent
destruction of the involved structures. Patients
usually consult primary care physicians,
otolaryngologists,
rheumatologists
and
ophthalmologists. On average, it takes 3 years
between occurrence of the first symptom until
RP is diagnosed. This gap reflects the diagnostic
ambiguities that may encountered. Thus,
proposed diagnostic criteria for RP are based on
characteristic clinical manifestations.
Empirical diagnostic criteria have been
established by McAdam et al. (6), Michet et al.
(7) and Damiani et al. (8). The diagnostic criteria
proposed by McAdam require three or more
clinical
features,
even
without
biopsy
confirmation (Table 1). Damiani and Levine have
suggested that diagnosis can be considered as
definitive when one or more of the clinical
features are present in conjunction with biopsy
confirmation.
Table 1. Diagnostic criteria for relapsing polychondritis
(6)
Recurrent chondritis of both auricles
Non erosive inflammatory polyarthritis
Chondritis of nose cartilage
Inflammation of ocular structures
keratitis, scleritis, episcleritis, uveitis
Chondritis of the respiratory tract
laryngeal and/or tracheal cartilages
Cochlear and/or vestibular damage causing sensor neural
hearing loss, tinnitus and/or vertigo
Differential diagnosis
Although the clinical features of this disease are
characteristic, diagnosis may be difficult in some
cases. Thus, acute streptococcal infection,
fungal infection, Hansen disease, and syphilis
may all lead to perichondritis that can be easily
misdiagnosed as RP. Auricular involvement must
also be differentiated from traumatic and
chemical conditions, such as frostbite and insect
bite. Prolonged endotracheal intubation may
cause tracheal injury similar to that of RP (5-8).
Nasal damage may occur in many other
conditions such as local infections from fungi,
tuberculosis, syphilis, leprosy, Wegener’s
granulomatosis and lethal midline granuloma
and should be taken into account (9, 12). Eye
involvement in RP can be difficult to differentiate
from other conditions like keratitis and scleritis,
which may occur in rhumatoid arthritis,
Wegener’s granulomatosis, polyarteritis nodosa,
Behçet’s disease, and Cogan’s disease (5-7, 11,
12).
Prevalence
In Rochester (Minnesota), the estimated annual
incidence rate was 3.5/million. The peak age for
disease onset is the fifth decade, although cases
have been reported at both extremes of life (5).
Most cases occur in whites. Both pediatric and
elderly cases have been described with an age
range of 6 to 87 years. Pregnancy does not
seem to influence the disease course and the
majority of pregnancies were successful (13). RP
was reported to occur with equal frequency in
both sexes. However, some authors found that
the female/male ratio was about 3:1 (5) (Table
2).
Table 2. Clinical features of patients with
relapsing polychondritis in 4 large series
Mc
Adam
(6)
[1976]
Variables: total
number of patients N= 159
followed up
Mean age at
44
diagnosis (years)
Female/male
1/1
Mean duration of
follow up (years)
Ear involvement
(%)
auricular chondritis
27
7
auditory
dysfunction
vestibular
dysfunction
Polyarthritis (%)
24
Nasal chondritis
14
(%)
Ocular
15
inflammation (%)
Respiratory tract
15
inflammation (%)
Cardiovascular
9
inflammation (%)
Drosos A.A. Relapsing polychondritis. Orphanet encyclopedia, May 2004.
http://www.orpha.net/data/patho/GB/uk-RP.pdf
Michet
(7)
[1986]
Zeuner
(10)
[1997]
Trentham
(5) [1998]
N= 112
N= 62
N= 66
51
47
46
1/1
1.8/1
3/1
6
-
8
40
9
4
93.5
19
23
92
7
6
37
53
48
25
56.5
33
20
50
25
26
31
39
1
23
1
2
Skin involvement
(%)
Kidney disease
(%)
Nervous system
involvement (%)
17
7
-
0.5
-
-
6.5
-
-
-
10
-
Clinical description
Associated diseases
In about one third of patients, RP is associated
with vasculitis and autoimmune rheumatic
diseases (Table 3) (14). The most commonly
reported types of vasculitis range from isolated
cutaneous leucocytoclastic vasculitis to systemic
polyangiitis. Vessels of all sizes may be affected
and large-vessel vasculitis is a well-recognized
and potentially fatal complication. The MAGIC
syndrome (mouth and genital ulcers with
inflamed cartilage) has also been reported to be
associated with RP (5). The second most
commonly associated disorder is autoimmune
rheumatic diseases mainly rheumatoid arthritis
(RA) and systemic lupus erythematosus (SLE)
(5). Other disorders associated with RP are
hematological
malignant
diseases,
gastrointestinal disorders, endocrine diseases
and others (Table 3).
Table 3. Conditions associated with relapsing
polychondritis
Vasculitis
Leucocytoclastic
Wegener’s granulomatosis
Polyarteritis nodosa
Churg-Strauss
MAGIC syndrome
Behçet’s disease
Mixed cryoglobulinemia
Autoimmune rheumatic
diseases
Rheumatoid arthritis
Systemic lupus
erythematosus
Sjögren’s syndrome
Mixed connective tissue
disease
Seronegative
spondylarthophathies
Ankylosing spondylitis
Psoriatic arthritis
Reiter’s syndrome
Gastrointestinal diseases
Crohn’s disease
Ulcerative colitis
Primary biliary cirrhosis
Retroperitonial fibrosis
Hematological diseases
Myelodysplastic syndromes
Hodgkin’s disease
Non Hodgkin’s lymphoma
Acute lymphoblastic
leukemia
Pernicious anemia
Endocrine disorders
Diabetes mellitus type I
Hashimoto thyroiditis
Graves disease
Hypothyroidism
Dermatological disorders
Psoriasis
Pyoderma gangrenosum
Vitiligo
Panniculitis
Atopic dermatitis
Lichen planus
Other diseases
Myasthenia gravis
Familiar mediterranian fever
Thymoma
Clinical features
The demographic and clinical features of
patients with RP are summarized in 4 large
series in table 2. Disease onset is generally
sudden and often flagrant. External ear
involvement is the presenting symptom in
almost all patients. RP typically attacks the
cartilaginous portion of the pinna, sparing the
lobe which lacks cartilage. Auricular chondritis
presents with pain, redness or violaceous
discoloration, swelling and tenderness involving
one or both ears. Episodes can last a few days
or weeks and patients recover from these
episodes with or without treatment. After
recurrent or persistent inflammation, the disease
ends in cartilage destruction. The pinna loses its
firmness, becomes soft and flops over or has a
knobby or cauliflower appearance (5-8, 10-12).
Hearing impairment may accompany ear
involvement. This is due to closure of the
external auditory meatus, serous otitis media
and Eustachian tube obstruction. In addition,
inflammation of the middle ear with sensorineural
hearing loss and vestibular dysfunction with
dizziness, ataxia, nausea and vomiting may also
occur. In table 2, the main clinical features are
presented from four large series (5-7, 10-12).
The second most common clinical finding of
RP is joint pain with or without arthritis. All
synovial joints may be affected. The most
commonly
involved
joints
are
metacarpophalangeal, proximal interphalangeal
joints, wrists and knees mimicking RA. Mono or
oligoarthritis involving peripheral large joints also
occur. Arthritis is non-deforming and nonerosive. Tests for rheumatoid factor are negative
in affected patients (5-8, 10).
Involvement of the nasal cartilage may present
with nasal pain, redness and swelling. Repeated
attacks may cause destruction of the nasal
bridge creating the characteristic “saddle-nose”
deformity (5-7, 10, 12,15).
Ocular manifestations, occur in approximately
60% of reported patients with RP. The most
common are scleritis, episcleritis, keratitis and
conjuctivitis,
which
may
occur
early.
Recurrences and exacerbations are very
common. Scleritis and episcleritis usually parallel
inflammation elsewhere, most commonly of the
nose and joints (16). Uveitis occurs in about 25%
of RP patients and 15 most often either an
anterior uveitis or a sclerouveitis (16). Additional
ocular manifestations include proptosis, corneal
perforation, retinal vasculitis and optic neuritis
leading to blindness (5-7, 13,16).
Respiratory symptoms are common and can
be lethal. At disease onset, approximately 25%
of the patients present with respiratory
symptoms, while during disease course, this
precentage increases to 50%. Inflammation
occurs in the laryngeal, tracheal and bronchial
cartilages which is accompanied by complaints
Drosos A.A. Relapsing polychondritis. Orphanet encyclopedia, May 2004.
http://www.orpha.net/data/patho/GB/uk-RP.pdf
3
of hoarseness, non productive cough, dyspnea,
wheezing and inspiratory stridor (5-8, 12,15).
Early in the disease, patients may have
tenderness over the thyroid cartilage and
trachea. Involvement of laryngeal and epiglottal
cartilage may lead to upper airway collapse,
which may require emergency tracheostomy.
Strictures usually appear in the subglottic region,
causing increased susceptibility to secondary
infections.
Mortality
from
respiratory
complications varies from 10 to 50%.
Cardiovascular
involvement,
although
uncommon, is the second most frequent cause
of death in patients with RP. Aortic regurgitation
and mitral regurgitation occur in about 2 to 6% of
the patients. Aortic regurgitation is more often
attributable to progressive dilation of the aortic
root of the ascending aorta than to inflammation
of the valve leaflets. Rarely, dilation of the
annulus of both mitral and tricuspid valves may
cause mitral and tricuspid regurgitation (5-8, 17).
Other manifestations include thoracic and
abdominal aneurysm, myocarditis, pericarditis,
silent myocardial infection, paroxysmal atrial
tachycardia, and first-degree or even complete
heart block.
Renal involvement can occur in RP in the
absence of other associated diseases such as
SLE or systemic vasculitis. Although rare, renal
disease indicates worse prognosis. The most
common histopathologic finding is mild
mesangial proliferation, followed by focal and
segmental necrotizing glomerulonephritis with
crescents.
Other
abnormalities
include
glomerulosclerosis, IgA nephropathy and
tubulointertitial nephritis. Immunofluorescence
studies most often reveal faint deposits of C3,
IgG or IgM primarily in the mesangium (5, 15).
Neurological abnormalities, not due to
infection, rarely occur in patients with RP. The
most common manifestations are cranial nerve
palsies, cerebral aneurysms and aseptic
meningitis (5-8). The pathogenesis of these
symptoms is presumed to be vasculitis, but
definite central nervous system vasculitis is
rarely documented. Magnetic resonance imaging
of the brain may show multifocal areas of
enhancement consistent with cerebral vasculitis
(11, 12).
Skin manifestations, RP causes many nonspecific skin disorders, which may proceed the
disease onset (chondritis) by 10 days to 20
years. Dermatologic symptoms are present in
50% of patients with RP. The frequency of skin
involvement in the absence of an associated
disease is about 35% but doubles in the
presence of another systemic illness. In a recent
study of 200 cases of RP, oral aphthous ulcers
were the most frequent manifestation, followed
by nodules on the limbs with an erythema
nodosum appearance (19).
Other
skin
manifestations
included:
purpura,
sterile
pustules, superficial phlebitis and livedo
reticularis. Limb ulcerations, urticarial papules,
bluish red papules, distal necrosis and erythema
elevatum diutinum were seen less frequently
(19).
Biopsy
specimens
often
show
leucocytoclastic,
nercotizing
or
even
granulomatosus vasculitis (5,19).
Additional symptoms, such as fatigue and
weight loss, are common in RP and fever
frequently accompanies acute flares (5).
Laboratory findings
During acute flares, patients may present with
markers of inflammation, such as elevated
erythrocyte sedimentation rate, and C-reactive
protein,
anemia,
leucocytosis
and
thrombocytosis. Serum antibodies to collagen II
have been found in about 40% to 50% of the
patients
with
RP
(20).
Urinary
glycosaminoglycans levels may be elevated.
Recently, a serum 148-kDa noncollageneous
cartilage matrix protein has been identified in
patients with RP and RA. In patients with RP,
tests for rheumatoid factor, antinuclear
antibodies
or
antineutrophil
cytoplasmic
antibodies are negative, unless an associated
autoimmune disease occurs. Conventional
radiographs and computed tomography identified
laryngotracheal lesions and thin section
computed tomography defines abnormalities in
lobar and segmental bronchi. Three-dimensional
or spiral magnetic resonance imaging may
provide better resolution. Pulmonary function
tests are useful tools for monitoring changes
over time. Finally, biopsy from ear cartilage or
other inflamed areas may be useful to confirm
the diagnosis.
Prognosis
Relapsing polychondritis is generally a
progressive disease. The majority of the patients
experience intermittent or fluctuant inflammatory
manifestations. Many have persistent symptoms
between acute flares. Most of them develop
some degree of disability over the time. It
includes bilateral deafness, impaired vision,
phonation difficulties and respiratory problems.
In 1986, the overall survival rates were 74% at 5
years and 55% at 10 years. However, recent
studies showed a better outcome with a survival
rate of 94% at 8-year follow-up (5-8). Pneumonia
is the most common cause of death related to
RP. These cases are often associated with
airway stricture and long-term steroid use. Other
causes of death include respiratory failure from
airway collapse or obstruction and complications
Drosos A.A. Relapsing polychondritis. Orphanet encyclopedia, May 2004.
http://www.orpha.net/data/patho/GB/uk-RP.pdf
4
of valvular heart disease and vasculitis (5-8, 1012).
than 30% of the patients with valvular
regurgitation need valve replacement (5).
Management
Patients with mild signs of acute inflammation
are usually treated with non-steroidal antiinflammatory drugs and small doses of
prednisone. Patients with severe manifestations,
such as airway compromise may require high
doses of prednisone (1 mg/kg/day) or even
intravenous pulse methyl-prednisone in doses of
1 g/day (5-8, 10-12). The doses are then tapered
to the lowest amounts that can prevent relapses.
Whether steroid therapy should be continued
during clinical remission periods remains
unclear. Several immunosuppressive drugs have
been used in patients who developed resistance
to steroids and in patients who benefit from
steroid
sparing
regimens.
Azathioprine,
cyclosporine-A and plasmapheresis have all
been used as adjunctive therapies. Methotrexate
has been an efficacious and well-tolerated
steroid sparing medication. Trentham et al.
reported 23 out of 31 patients receiving
methotrexate, at an average dose of 17.5
mg/week, responded very well and were able to
taper their prednisone dose from 19 mg/day to 5
mg/day (5). Dapsone (50 to 200 mg/day) has
been advocated as an effective therapy for
patients without cardiopulmonary involvement
(5). Other approaches include the use of Dpenicillamine, colchicine or even combination
therapy such as dapsone and steroids,
methotrexate, steroids and cyclosporine-A.
In patients with signs and features of systemic
vasculitis, cyclophosphamide may be useful.
More recently, anti-CD4 monoclonal antibody
was reported to be effective in two patients with
RP. Oral minocycline, as used for treating RA,
was associated with improvement in a patient
who had developed methotrexate toxicity (5).
A recent report describes a child successfully
treated with daily oral fetal bovine type II
collagen. Although, this is only a case report, the
favorable safety profile of oral type II collagen
makes it deserving of further study (21). Several
biological therapies have been tried in RP. An
anti-CD4 chimeric monoclonal antibody has
been successful as a salvage therapy. Infliximab
has been reported to induce remission in some
cases (22). When other treatments fail,
autologus stem cell transplantation may induce
remission in RP patients (11, 12).
Patients
who
develop
cardiorespiratory
complications despite medical therapy may
require surgery. Tracheostomy or stenting may
be required to alleviate localized or extensive
trancheobronchial disease. In addition, more
Etiology
The cause of RP remains unknown. Specimens
of inflamed cartilage may show distinctive
features. There is a loss of basophilic staining of
the
cartilage
matrix
accompanied
by
perichondral inflammation of the cartilage.
Perivascular
mononuclear
and
polymorphonuclear cell infiltrates are present.
The chondrocytes become vacuolated and
necrotic and are eventually replaced by fibrous
tissue (23).
Experimental studies in rabbits have shown that
the intravenous injection of papain causes
collapse of the external ear within a few hours. In
addition, cartilage tissue shows loss of
metachromatic staining without inflammation. In
humans, cartilage destruction results from the
release of degradative enzymes, including matrix
metalloproteinases
and
reactive
oxygen
metabolites
from
inflammatory
cells,
chondrocytes and other cellular elements. The
release of these enzymes is likely to be
secondary to immune mediated activation of
chondrocytes and other inflammatory cells by
cytokines including interleukin-1 (IL-1)and tumor
necrosis factor alpha (TNF-a). Pathogenesis of
RP is unknown. However, autoimmunity is
involved in several ways:
1) Tissue inflammation is composed of
macrophages, CD4+ lymphocytes and B cells. In
addition, deposition of immunoglobulins and
complement components are found in tissue
lesions of patients with RP.
2) Antibodies to type II collagen, as well as type
IX and XI collagen are found in the sera of
patients with RP (20). T cell clones isolated from
a patient with RP were found to be specific for
type II collagen peptide 261-273 (24).
3) Immunization of rodents with collagen II and
immunization of rats with cartilage matrix protein
(matrillin-1) results in the development of
auricular chondritis and tracheal cartilage
inflammation respectively (25-27).
4) Association with autoimmune diseases and
HLA class II molecules (DR4) have been
reported.
5) The tissue specificity of RP suggests that
antigens derived from cartilage play an important
role in driving and propagating the disease. Thus
the following hypothesis may emerge.
In a genetically predisposed individual, an
unknown x factor may cause immunological
response to tissues rich in type II collagen and
matrillin-1 (25-27). This leads to an inflammatory
process of the cartilage, which causes cytokine
and autoantibody production and immune
Drosos A.A. Relapsing polychondritis. Orphanet encyclopedia, May 2004.
http://www.orpha.net/data/patho/GB/uk-RP.pdf
5
response perpetuation. This may cause
chondrocyte damage, release of proteolytic
enzymes, cartilage destruction and disease
expression.
Genetic findings
Recent studies revealed significant association
of RP with HLA-DR4 antigen. There was no
predominance of any of the DRB1*04 subtype
alleles in these patients (10). Additionally, no
HLA-DR1 association was found. This contrasts
with RA, where clear association with DRB1*0401 and DRB1*0404 has been established.
Therefore, the shared epitope hypothesis, as
postulated for RA, is not likely to be true for RP.
Diagnostic methods
No specific diagnostic tools are required for the
diagnosis of RP. Serum autoantibodies to
collagen II and to 148-kDa noncollageneous
cartilage matrix protein may be helpful. Chest
conventional radiographs, pulmonary function
test and chest CT tomography may be useful for
diagnosis. Finally, cartilage biopsy from ear or
other inflamed tissues may be useful to confirm
the diagnosis.
Genetic counseling
Genetic counseling is not available.
Unresolved questions
Origin of the unknown etiological factor.
Role of collagen II and matrillin-1 in disease
pathogenesis.
Perpetuation and activation of the immune
system.
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